Search

Although it is often assumed that preinjury anticoagulant (AC) or antiplatelet (AP) use is associated with poorer outcomes among those with acute subdural hematoma (aSDH), previous studies have had varied results. This study examines the impact of preinjury AC and AP therapy on aSDH thickness, 30-day mortality, and extended Glasgow Outcome Scale at 6 months in elderly patients (aged ≥65).A level 1 trauma center registry was interrogated to identify consecutive elderly patients who presented with moderate or severe traumatic brain injury (TBI) and associated traumatic aSDH between the first of January 2013 and the first of January 2018. Relevant demographic, clinical, and radiological data were retrieved from institutional medical records. The 3 primary outcome measures were aSDH thickness on initial computed tomography scan, 30-day mortality, and unfavorable outcome at 6 months (extended Glasgow Outcome Scale).One hundred thirty-two elderly patients were admitted with moderate or severe TBI and traumatic aSDH. The mean (±SD) age was 78.39 (±7.87) years, and a majority of patients (59.8%, n = 79) were male. There was a statistically significant difference in mean aSDH thickness, but there were no significant differences in 30-day mortality (P = 0.732) and unfavorable outcome between the AP, AC, combined AP and AC, and no antithrombotic exposure groups (P = 0.342).Further studies with larger sample sizes are necessary to confirm these observations, but our findings do not support the preconceived notion in clinical practice that antithrombotic use is associated with poor outcomes in elderly patients with moderate or severe TBI.

We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1–3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1–3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1–3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.

Background Studies from high income countries suggest improved survival for females as compared to males following trauma. However, data regarding differences in trauma outcomes between females and males is severely lacking from low- and middle-income countries. The objective of this study was to determine the association between sex and clinical outcomes amongst Indian trauma patients using the Australia-India Trauma Systems Collaboration database. Methods A prospective multicentre cohort study was performed across four urban public hospitals in India April 2016 through February 2018. Bivariate analyses compared admission physiological parameters and mechanism of injury. Logistic regression assessed association of sex with the primary outcomes of 30-day and 24-hour in-hospital mortality. Secondary outcomes included ICU admission, ICU length of stay, ventilator requirement, and time on a ventilator. Results Of 8,605 patients, 1,574 (18.3%) were females. The most common mechanism of injury was falls for females (52.0%) and road traffic injury for males (49.5%). On unadjusted analysis, there was no difference in 30-day in-hospital mortality between females (11.6%) and males (12.6%, p = 0.323). However, females demonstrated a lower mortality at 24-hours (1.1% vs males 2.1%, p = 0.011) on unadjusted analysis. Females were also less likely to require a ventilator (17.3% vs 21.0% males, p = 0.001) or ICU admission (34.4% vs 37.5%, p = 0.028). Stratification by age or by ISS demonstrated no difference in 30-day in-hospital mortality for males vs females across age and ISS categories. On multivariable regression analysis, sex was not associated significantly with 30-day or 24-hour in-hospital mortality. Conclusion This study did not demonstrate a significant difference in the 30-day trauma mortality or 24-hour trauma mortality between female and male trauma patients in India on adjusted analyses. A more granular data is needed to understand the interplay of injury severity, immediate post-traumatic hormonal and immunological alterations, and the impact of gender-based disparities in acute care settings.

The present study aimed to determine the difference in force required to puncture simulated pleura comparing Kelly clamps to fine artery forceps. The treatment of symptomatic traumatic pneumothorax and haemothorax involves puncture of the parietal pleura to allow decompression. This is usually performed using Kelly clamps or fine artery forceps. Over-puncture pulmonary injury risk increases with the force used.An experienced single operator performed puncturing of simulated parietal pleura on a thoracic mannequin while wearing a force sensor under gloves. The force imparted at the device tip onto the parietal pleura was estimated by subtracting the force required to hold the device from the total force. Outcome variables were the total maximum force and force imparted by the device.There were 11 simulated procedures completed, seven using Kelly clamps and four using fine artery forceps. After subtracting the force required to hold the chosen forceps, the median value of pleural puncture force using Kelly clamps was 52.91 N (IQR 36.68-63.56) and 10.70 N (IQR 7.64-26.56) using fine artery forceps (P = 0.006).A significantly increased force was required to puncture simulated parietal pleura using Kelly clamps compared to fine artery forceps. This higher puncture force will be associated with increased instrument acceleration at the time of pleural puncture, which may result in an increased risk of injury to the underlying lung. Based on these data, clinicians may reduce the risk of pulmonary injury by using fine artery forceps rather than Kelly clamps when performing pleural decompression.

Summary Mass casualty incidents (MCIs) are diverse, unpredictable, and increasing in frequency, but preparation is possible and necessary. The nature of MCIs requires a trauma response but also requires effective and tested disaster preparedness planning. From an international perspective, the aims of this narrative review are to describe the key components necessary for optimisation of trauma system preparedness for MCIs, whether trauma systems and centres meet these components and areas for improvement of trauma system response. Many of the principles necessary for response to MCIs are embedded in trauma system design and trauma centre function. These include robust communication networks, established triage systems, and capacity to secure centres from threats to safety and quality of care. However, evidence from the current literature indicates the need to strengthen trauma system preparedness for MCIs through greater trauma leader representation at all levels of disaster preparedness planning, enhanced training of staff and simulated disaster training, expanded surge capacity planning, improved staff management and support during the MCI and in the post-disaster recovery phase, clear provision for the treatment of paediatric patients in disaster plans, and diversified and pre-agreed systems for essential supplies and services continuity. Mass casualty preparedness is a complex, iterative process that requires an integrated, multidisciplinary, and tiered approach. Through effective preparedness planning, trauma systems should be well-placed to deliver an optimal response when faced with MCIs.

Background The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population. Methods PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older—or aged 18 years or older with relevant comorbidities—and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031. Findings Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81–1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir. Interpretation Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community. Funding UK National Institute for Health and Care Research

ObjectiveThis study explored the perspectives and behaviours of emergency physicians (EPs), regularly involved in resuscitation, to identify the sources and effects of any stress experienced during a resuscitation as well as the strategies employed to deal with these stressors.MethodsThis was a two-centre sequential exploratory mixed-methods study of EPs consisting of a focus group, exploring the human factors related to resuscitation, and an anonymous survey. Between April and June 2020, the online survey was distributed to all EPs working at Australia’s largest two major trauma centres, both in Melbourne, and investigated sources of stress during resuscitation, impact of stress on performance, mitigation strategies used, impact of the COVID-19 pandemic on stress and stress management training received. Associations with gender and years of clinical practice were also examined.Results7 EPs took part in the focus group and 82 responses to the online survey were received (81% response rate). The most common sources of stress reported were resuscitation of an ‘unwell young paediatric patient’ (81%, 95% CI 70.6 to 87.6) or ‘unwell pregnant patient’ (71%, 95% CI 60.1 to 79.5) and ‘conflict with a team member’ (71%, 95% CI 60.1 to 79.5). The most frequently reported strategies to mitigate stress were ‘verbalising a plan to the team’ (84%, 95% CI 74.7 to 90.5), ‘implementing a standardised/structured approach’ (73%, 95% CI 62.7 to 81.6) and ‘asking for help’ (57%, 95% CI 46.5 to 67.5). 79% (95% CI 69.3 to 86.6) of EPs reported that they would like additional training on stress management. Junior EPs more frequently reported the use of ‘mental rehearsal’ to mitigate stress during a resuscitation (62% vs 22%; pConclusionsStress is commonly experienced by EPs during resuscitation and can impact decision-making and procedural performance. This study identifies the most common sources of stress during a resuscitation as well as the strategies that EPs use to mitigate the effects of stress on their performance. These findings may contribute to the development of tailored stress management training for critical care clinicians.

OBJECTIVE A supraglottic airway device (SAD) may be utilised for rescue re-oxygenation following a failed attempt at endotracheal intubation with direct or video laryngoscopy. However, the choice of subsequent method to secure a definitive airway is not clearly established. The aim of the present study was to compare two techniques for securing a definitive airway via the in-situ SAD. METHODS A randomised controlled trial was undertaken. The population studied was emergency physicians (EPs) attending a cadaveric airway course. The intervention was intubation through a SAD using a retrograde intubation technique (RIT). The comparison was intubation through a SAD guided by a flexible airway scope (FAS). The primary outcome was time to intubation. The trial was registered with ANZCTR.org.au (ACTRN12621000995875). RESULTS Four EPs completed intubations using both methods on four cadavers for a total of 32 experiments. The mean time to intubation was 18.2 s (standard deviation 8.8) in the FAS group compared with 52.9 s (standard deviation 11.7) in the RIT group; a difference of 34.7 s (95% confidence interval 27.1-42.3, P

Introduction Injury is a major global health burden. Trauma registries have been used for decades to monitor the burden of injury and inform trauma care. However, the extent to which trauma registries have fulfilled their potential remains uncertain. The aims of this study were to determine the current and priority uses of trauma registries across Australia and New Zealand and to establish the priority clinical outcomes, the probability for which, if known for an individual trauma patient, would better inform that same patient's care, during hospital admission. Methods A prospective observational study using survey methodology was conducted. Participants were sourced from the Australia New Zealand Trauma Registry (ATR) participating hospitals. The survey questions included: the current uses and priorities for both single-site trauma registries and the binational trauma registry; the five top-ranked priority outcomes for which knowing the probability, for an individual patient, would inform care; and the priority timepoints for applying patient-level outcome prediction models. Results Of the 26 ATR-participating hospitals, 25 were represented by a total of 54 participants in the survey, including trauma service directors and trauma nurse coordinators. The main trauma registry use and priority for the single site registries was to inform the quality improvement program; for the ATR, the main use was periodic reporting and the main priority was benchmarking. For each potential purpose of the registry, the future priority level was ranked more highly than the current level of utilisation. The most highly ranked priority patient-level outcomes requiring prediction were: preventable death, missed injury, quality of life, admission costs, pulmonary embolism, post-traumatic stress disorder, length of hospital stay, errors in decision-making and deep venous thrombosis. The time period between leaving the emergency department and the 24 h mark following presentation was considered the preferred time for patient-level priority outcome prediction. Conclusion There is a mismatch between current trauma registry uses and future priorities. The priority outcomes demanding prediction in the first 24 h of a trauma patient's stay are preventable death, missed injury, quality of life, hospital costs, thromboembolism, post-traumatic stress disorder, length of hospital stay and errors in clinical decision-making.

Fractional exhaled nitric oxide (FeNO) has potential as a prognostic biomarker in asthma, but its prognostic value among other recognised indicators is unclear. We assessed the added prognostic value of baseline FeNO to blood eosinophil count and prior severe asthma exacerbations for subsequent exacerbations.In this post-hoc analysis of the 52-week, double-blind, phase 3 LIBERTY ASTHMA QUEST study, we identified 620 patients with moderate-to-severe asthma who were randomly assigned to placebo; had uncontrolled asthma with inhaled glucocorticoids plus up to two controllers; one or more exacerbations in the previous year; FEVPatients with baseline FeNO of 50 ppb or higher (n=144) had a 1·54-times higher exacerbation rate than patients with FeNO of less than 25 ppb (n=291; relative risk 1·54 [95% CI 1·11-2·14]; p=0·0097). Patients with baseline FeNO of 25 to50 ppb (n=185) had a 1·33-times higher exacerbation rate than patients with FeNO of less than 25 ppb (1·33 [0·99-1·78]; p=0·0572). Patients with baseline FeNO of 25 ppb or higher, a blood eosinophil count of 150 cells per μL or higher, and two or more prior exacerbations (n=157) had an exacerbation rate 3·62-times higher than patients with FeNO of less than 25 ppb, a blood eosinophil count of less than 150 cells per μL, and one prior exacerbation (n=116; 3·62 [1·67-7·81]; p=0·0011).In uncontrolled, moderate-to-severe asthma, higher baseline FeNO levels were associated with greater risk of severe asthma exacerbations, particularly in combination with elevated eosinophil count and prior exacerbations, supporting the added value of FeNO as a prognostic biomarker. Further research is needed to confirm FeNO as an independent predictor for asthma exacerbations.Sanofi and Regeneron Pharmaceuticals.

Background In patients with a history suggestive of asthma, diagnosis is usually confirmed by spirometry with bronchodilator response (BDR) or confirmatory methacholine challenge testing (MCT). Research Question We examined the proportion of participants with negative BDR testing who had a positive MCT (and its predictors) result and characteristics of MCT, including effects of controller medication tapering and temporal variability (and predictors of MCT result change), and concordance between MCT and pulmonologist asthma diagnosis. Study Design and Methods Adults with self-reported physician-diagnosed asthma were recruited by random-digit dialing across Canada. Subjects performed spirometry with BDR testing and returned for MCT if testing was nondiagnostic for asthma. Subjects on controllers underwent medication tapering with serial MCTs over 3 to 6 weeks. Subjects with a negative MCT (the provocative concentration of methacholine that results in a 20% drop in FEV1 [PC20] > 8 mg/mL) off medications were examined by a pulmonologist and had serial MCTs after 6 and 12 months. Results Of 500 subjects (50.5 ± 16.6 years old, 68.0% female) with a negative BDR test for asthma, 215 (43.0%) had a positive MCT. Subjects with prebronchodilator airflow limitation were more likely to have a positive MCT (OR, 1.90; 95% CI, 1.17-3.04). MCT converted from negative to positive, with medication tapering in 18 of 94 (19.1%) participants, and spontaneously over time in 25 of 165 (15.2%) participants. Of 231 subjects with negative MCT, 28 (12.1%) subsequently received an asthma diagnosis from a pulmonologist. Interpretation In subjects with a self-reported physician diagnosis of asthma, absence of bronchodilator reversibility had a negative predictive value of only 57% to exclude asthma. A finding of spirometric airflow limitation significantly increased chances of asthma. MCT results varied with medication taper and over time, and pulmonologists were sometimes prepared to give a clinical diagnosis of asthma despite negative MCT. Correspondingly, in patients for whom a high clinical suspicion of asthma exists, repeat testing appears to be warranted.

PURPOSE/OBJECTIVES The aim of this study is to report data on the lack of a proper patient handoff system in dentistry and dental education and to present a possible solution to integrate this into curriculum using the "entrustable professional activities" (EPAs) framework. METHODS Delphi participants from seven US dental schools provided feedback on a preliminary definition of handoff, a mnemonic and an assessment rubric. 2019 American Dental Education Association Commission on Change and Innovation in Dental Education (ADEA CCI) participants further evaluated the handoff EPA using the EQual rubric for EPA quality and structure. RESULTS Delphi participants identified points of transition in dentistry, selected the D-PASS as a mnemonic, and agreed with the evaluation rubric. The ADEA CCI participants agreed the handoff EPA describes work that is essential for the profession and suitable for entrustment. CONCLUSION The D-PASS rubric is an effective way to assess patient handoffs.

Osseointegration implant has attracted significant attention as an alternative treatment for transfemoral amputees. It has been shown to improve patients’ sitting and walking comfort and control of the artificial limb, compared to the conventional socket device. However, the patients treated with osseointegration implants require a long rehabilitation period to establish sufficient femur–implant connection, allowing the full body weight on the prosthesis stem. Hence, a robust assessment method on the osseointegration process is essential to shorten the rehabilitation period and identify the degree of osseointegration prior to the connection of an artificial limb. This paper investigates the capability of a vibration-related index (E-index) on detecting the degree of simulated osseointegration process with three lengths of the residual femur (152, 190 and 228 mm). The adhesive epoxy with a setting time of 5 min was applied at the femur–implant interface to represent the stiffness change during the osseointegration process. The cross-spectrum and colormap of the normalised magnitude demonstrated significant changes during the cure time, showing that application of these plots could improve the accuracy of the currently available diagnostic techniques. Furthermore, the E-index exhibited a clear trend with a noticeable average increase of 53% against the cure time for all three residual length conditions. These findings highlight that the E-index can be employed as a quantitative justification to assess the degree of osseointegration process without selecting and tracing the resonant frequency based on the geometry of the residual femur.

Background Coronavirus disease 2019 (COVID-19) has exposed the disproportionate effects of pandemics on frontline workers and the ethical imperative to provide effective prophylaxis. We present a model for a pragmatic randomised controlled trial (RCT) that utilises Bayesian methods to rapidly determine the efficacy or futility of a prophylactic agent. Methods We initially planned to undertake a multicentre, phase III, parallel-group, open-label RCT, to determine if hydroxychloroquine (HCQ) taken once a week was effective in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in healthcare workers (HCW) aged ≥ 18 years in New Zealand (NZ) and Ireland. Participants were to be randomised 2:1 to either HCQ (800 mg stat then 400 mg weekly) or no prophylaxis. The primary endpoint was time to Nucleic Acid Amplification Test-proven SARS-CoV-2 infection. Secondary outcome variables included mortality, hospitalisation, intensive care unit admissions and length of mechanical ventilation. The trial had no fixed sample size or duration of intervention. Bayesian adaptive analyses were planned to occur fortnightly, commencing with a weakly informative prior for the no prophylaxis group hazard rate and a moderately informative prior on the intervention log hazard ratio centred on ‘no effect’. Stopping for expected success would be executed if the intervention had a greater than 0.975 posterior probability of reducing the risk of SARS-CoV-2 infection by more than 10%. Final success would be declared if, after completion of 8 weeks of follow-up (reflecting the long half-life of HCQ), the prophylaxis had at least a 0.95 posterior probability of reducing the risk of SARS-CoV-2 infection by more than 10%. Futility would be declared if HCQ was shown to have less than a 0.10 posterior probability of reducing acquisition of SARS-CoV-2 infection by more than 20%. Discussion This study did not begin recruitment due to the marked reduction in COVID-19 cases in NZ and concerns regarding the efficacy and risks of HCQ treatment in COVID-19. Nonetheless, the model presented can be easily adapted for other potential prophylactic agents and pathogens, and pre-established collaborative models like this should be shared and incorporated into future pandemic preparedness planning. Trial registration The decision not to proceed with the study was made before trial registration occurred.

Objective In response to COVID‐19, we introduced and examined the effect of a raft of modifications to standard practice on adverse events and first‐attempt success (FAS) associated with ED intubation. Methods An analysis of prospectively collected registry data of all ED intubations over a 3‐year period at an Australian Major Trauma Centre. During the first 6 months of the COVID‐19 pandemic in Australia, we introduced modifications to standard practice to reduce the risk to staff including: aerosolisation reduction, comprehensive personal protective equipment for all intubations, regular low fidelity simulation with ‘sign‐off’ for all medical and nursing staff, senior clinician laryngoscopist and the introduction of pre‐drawn medications. Results There were 783 patients, 136 in the COVID‐19 era and 647 in the pre‐COVID‐19 comparator group. The rate of hypoxia was higher during the COVID‐19 era compared to pre‐COVID‐19 (18.4% vs 9.6%, P, Outcomes and disposition before and during COVID‐19.

Purpose/objectives The purpose of this study was to define and develop a set of Entrustable Professional Activities (EPAs) for dental education using a modified Delphi consensus approach. EPAs define the core tasks that a graduating dentist needs to perform independently in practice. The EPA framework facilitates assessment of competencies as they manifest in the tasks and independence needed to be ready for practice. Methods Feedback was obtained from participants about a list of EPAs, with modifications made after each of the 3 rounds, using a modified Delphi approach. Phase 1 included attendees at the ADEA Fall 2017 meeting (n = 35) who participated in an EPA workshop primarily composed of academic deans. The Phase 2 "reactor panel" consisted of 10 dental schools' academic deans and other individuals with expertise and interest in dental curriculum and assessment (n = 31). Phase 3 participants were attendees at the ADEA CCI 2019 meeting (n = 91) who also participated in a 2-day EPA workshop. Results In phase 1, overall ratings for acceptability of the EPAs were satisfactory. In phase 2, the next iteration of EPAs was judged as satisfactory for inclusion in curriculum, match well with clinical practice and clarity. In phase 3, the EPAs were judged as satisfactory for being an "entrustable, essential, and important task of the profession." Qualitative feedback suggested wording, measurability, and specific focus of EPA statements is important. Conclusions A preliminary set of EPAs was designed for predoctoral dental education through a systematic, careful consensus building approach involving a diverse set of participants.

Patients treated with splenic artery embolization (SAE) >48 hours after a blunt injury for a delayed splenic rupture (DSR) were assessed for the need for a subsequent splenectomy. Thirty-four patients underwent SAE for DSR over 10 years at our level 1 trauma center, performed at a median of 4.5 days after the injury (interquartile range = 5.5), and the patients were followed up for a median of 11 months (interquartile range = 31). There were 3 occurrences of rebleeds, and 2 patients required splenectomy (5.9%). This study showed that treatment with SAE after DSR results in splenic salvage in 94.1% of patients.

Introduction: Delayed Intracranial Hemorrhage (D-ICH), defined as finding of ICH on subsequent imaging after a normal computed tomography of the brain (CTB), is a feared complication after head tra...

BACKGROUND Bile leak following blunt liver trauma is uncommon. Management is difficult due to complex vasculo-biliary and liver parenchymal injury and lack of consensus on optimal care compared with bile leak following elective hepatectomy especially in regards to endoscopic retrograde pancreaticocholangiography (ERCP) timing and patient selection. METHODS This is a retrospective cohort study from a level 1-trauma centre of patients with bile leak following blunt liver injury between July 2010 and December 2019 identified from the trauma registry. Clinical data retrieved include patient demographics, injury severity score, liver injury grading and its associated complications and treatment. This was supplemented by surgical audit database and patients' electronic medical record. RESULTS There were 31 bile leaks amongst 639 patients with blunt liver trauma (4.9%). Bile leak was associated with higher liver injury grade (odds ratio (OR) 36, P = 0.001), hepatic embolization (OR 16, P = 0.003) and need for trauma laparotomy (OR 14, P = 0.024). ERCP was performed in 58.1% (n = 18). This was complicated in 27.7% (n = 5) by mild pancreatitis (n = 1) and intra-abdominal sepsis (n = 4) requiring surgical drainage of abscess (n = 2) and liver resection (n = 1). Bile leak settled conservatively (including percutaneous drainage) without ERCP in the remaining patients (41.9%). Overall mortality was not increased in those with bile leak (P = 0.998). CONCLUSION Bile leaks resolved conservatively in 41.9% of patients. Complications following ERCP were seen in 27.7%, frequently requiring intervention. Failure of conservative management was more likely in patients with hepatic embolization, in whom early ERCP remains appropriate. ERCP should otherwise be reserved for those who fail conservative management to minimize infective complications.

Background Emergency departments (ED) are challenging environments but critical for early management of patients with stroke. Purpose To identify how context affects the provision of stroke care in 26 Australian EDs. Method Nurses perceptions of ED context was assessed with the Alberta Context Tool. Medical records were audited for quality of stroke care and patient outcomes. Findings Collectively, emergency nurses (n = 558) rated context positively with several nurse and hospital characteristics impacting these ratings. Despite these positive ratings, regression analysis showed no significant differences in the quality of stroke care (n = 1591 patients) and death or dependency (n = 1165 patients) for patients in EDs with high or low rated context. Discussion Future assessments of ED context may need to examine contextual factors beyond the scope of the Alberta Context Tool which may play an important role for the understanding of stroke care and patient outcomes in EDs.

Purpose To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19). Methods Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable. Results We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (– 1 to 15), 0 (– 1 to 9) and—1 (– 1 to 7), respectively, compared to 6 (– 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively). Conclusion Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06448-5.

Asthma hospitalizations declined rapidly in many parts of the world, including Canada, in the 1990s and early 2000s.To examine whether the declining trend of asthma hospitalizations persisted in recent years in Canada.Using the Canadian comprehensive nationwide hospitalization data (2002-2017), we identified hospital admissions with the main International Classification of Diseases codes for asthma. We analyzed sex-specific age-standardized trends in annual hospitalization rates among pediatric (amp;lt; 19 years) and adult (19+ years) patients. We used change-point analysis to evaluate any substantial changes in the trends in the sex-age groups.There were 254,672 asthma-related hospital admissions (59% pediatric, 50% female) during the study period. Among children, age-adjusted annual rates per 100,000 decreased by 55% in females (152-69) and by 60% in males (270-108) from 2002 to 2017. Among adults, the rates decreased by 59% in both sexes (females: 61-25; males: 27-11). Change-point analysis indicated a substantial plateauing of the annual rate in both pediatric (from -15.3 [females] and -25.8 [males] before 2010 to -0.6 [females] and -0.8 [males] after 2010) and adult (from -5.4 [females] and -2.6 [males] before 2008 to -0.6 [females] and -0.2 [males] after 2008) groups.After a substantial decline in hospital admissions for acute asthma, there has been minimal further decline since 2010 for children and 2008 for adults. In addition to adhering to the contemporary standards of asthma care, novel, disruptive strategies are likely needed to further reduce the burden of asthma.

Background: Colchicine has been proposed as a COVID-19 treatment. Aim: To determine whether colchicine reduces time to recovery and COVID-19 related hospitalisations/deaths among people in the community. Design and setting: Prospective, multicentre, open-label, multi-arm, randomised, controlled adaptive platform trial (PRINCIPLE). Method: Adults aged ≥65, or ≥18 years with comorbidities or shortness of breath, and unwell ≤14 days with suspected COVID-19 in the community were randomised to usual care, usual care plus colchicine (500μg daily for 14 days), or usual care plus other interventions. The co-primary endpoints were time to first self-reported recovery, and hospitalisation/death related to COVID-19, within 28 days, analysed using Bayesian models. The hypothesis for the time to recovery endpoint is evaluated first, and if superiority is declared on time to recovery, the hypothesis for the second co-primary endpoint of hospitalisation/death is then evaluated. To determine futility, we pre-specified a clinically meaningful benefit in time to first reported recovery as a hazard ratio of 1.2 or larger (equating to approximately 1.5 days benefit in the colchicine arm, assuming 9 days recovery in the usual care arm). Results: The trial opened on April 2, 2020, with randomisation to colchicine from March 04, 2021 until May 26, 2021, after the pre-specified time to recovery futility criterion was met. The primary analysis model included 2755 SARS-CoV-2 positive participants, randomised to colchicine (n=156), usual care (n=1145), and other treatments (n=1454). Time to first self-reported recovery was similar in the colchicine group compared with usual care with an estimated hazard ratio of 0·919 [95% credible interval 0·72 to 1·16] and an estimated increase of 1.4 days in median time to self-reported recovery for colchicine versus usual care. The probability of meaningful benefit in time to recovery was very low at 1.8%. Results were similar in comparisons with concurrent controls. COVID-19 related hospitalisations/deaths were similar in the colchicine group versus usual care, with an estimated odds ratio of 0·76 [0·28 to 1·89] and an estimated difference of 0.4% [-2.4 to 2.7%]. One serious adverse event occurred in the colchicine group and two in usual care. Conclusions: Colchicine did not improve time to recovery in people at higher risk of complications with COVID-19 in the community.

Background: Patients with mild asthma represent a substantial proportion of the population with asthma, yet there are limited data on their true burden of disease. We aimed to describe the clinical and healthcare resource utilisation (HCRU) burden of physician-assessed mild asthma. Methods: Patients with mild asthma were included from the NOVEL observational longiTudinal studY (NOVELTY; NCT02760329), a global, 3-year, real-world prospective study of patients with asthma and/or chronic obstructive pulmonary disease from community practice (specialised and primary care). Diagnosis and severity were based on physician discretion. Clinical burden included physician-reported exacerbations and patient-reported measures. HCRU included inpatient and outpatient visits. Results: Overall, 2004 patients with mild asthma were included; 22.8% experienced >= 1 exacerbation in the previous 12 months, of whom 72.3% experienced >= 1 severe exacerbation. Of 625 exacerbations reported, 48.0% lasted >1 week, 27.7% were preceded by symptomatic worsening lasting >3 days, and 50.1% required oral corticosteroid treatment. Health status was moderately impacted (St George's Respiratory Questionnaire score: 23.5 [standard deviation +/- 17.9]). At baseline, 29.7% of patients had asthma symptoms that were not well controlled or very poorly controlled (Asthma Control Test score = 2 exacerbations in the previous year. In terms of HCRU, at least one unscheduled ambulatory visit for exacerbations was required by 9.5% of patients, including 9.2% requiring >= 1 emergency department visit and 1.1% requiring >= 1 hospital admission. Conclusions: In this global sample representing community practice, a significant proportion of patients with physician-assessed mild asthma had considerable clinical burden and HCRU.

Background Pancreatic trauma is rare and complex. Non-operative management of pancreatic injuries is often appropriate, and when surgical intervention is required there may be a choice between resectional or more conservative approaches. This is especially true for distal injuries. Operative management of proximal pancreatic injuries is extremely challenging and has less room for conservatism. We sought to characterize the surgical treatment of pancreatic injuries, comparing outcomes for those undergoing formal resection (FR) versus those undergoing more conservative surgical treatment. Our hypothesis was that 'biting the bullet' and resecting is not associated with worse outcomes than less invasive approaches. Methods All patients undergoing surgery for pancreatic injuries between June 2001 and June 2019 at the Alfred Hospital in Melbourne were included. Outcome measures including length of stay, return to theatre, total parenteral nutrition use, pancreatic fistula, intra-abdominal infection and mortality were compared between patients undergoing FR and those undergoing non-resectional procedures. Results Of nearly 60 000 trauma presentations, 194 patients sustained pancreatic injury and 51 underwent surgical intervention. Over 70% were secondary to blunt trauma. There were 27 FR and 22 non-resectional procedures. No major outcome differences were detected. FR was not associated with worse outcomes. Conclusion In distal injuries, where there is doubt regarding parenchymal viability or ductal integrity, FR can safely be performed with non-inferior outcomes to more conservative surgery. Patients with high-grade proximal injuries will usually have multiple other injuries and require resuscitation, temporization and staged reconstruction.

This study aimed to evaluate the utility of the 11-variable modified Frailty Index (mFI) in prognosticating elderly patients with traumatic acute subdural hematomas (aSDHs). A state-service level 1 trauma center registry was interrogated to investigate consecutive patients ≥65 years of age presenting with traumatic aSDH, with or without major extracranial injury, between January 2013 and December 2017. mFI on admission, demographics, and admission details, including Glasgow Coma Scale (GCS) and pupillary status and radiological findings, were retrospectively retrieved from institutional records. Clinical outcome data were retrieved from medical records and the Victorian State Trauma Registry (VSTR). Outcome measures were 1) 30-day mortality and 2) 6-month unfavorable outcome, defined by the Extended Glasgow Outcome Scale (GOS-E). Five hundred twenty-nine consecutive cases were identified from the registry. Demographic data included: 1) age (median; interquartile range) = 80.46; 74.17-85.89; 2) mFI (mean ± standard deviation) = 1.96 ± 1.42 of 11 variables. Four hundred sixteen cases (79%) had complete outcome data. As mFI increased from 0/11 variables to ≥5/11 variables (≥0.45), 30-day mortality risk increased from 17.72% to 39.29% (

Supplemental digital content is available in the text., BACKGROUND During hemorrhagic shock and subsequent resuscitation, pathways reliant upon calcium such as platelet function, intrinsic and extrinsic hemostasis, and cardiac contractility are disrupted. The objective of this systematic review was to examine current literature for associations between pretransfusion, admission ionized hypocalcemia, and composite outcomes including mortality, blood transfusion requirements, and coagulopathy in adult trauma patients. METHODS This review was reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. We searched Ovid MEDLINE and grey literature from database inception till May 3, 2020. Case series and reports were excluded. Reference lists of appraised studies were also screened for articles that the aforementioned databases might not have captured. The Newcastle-Ottawa Scale was used to assess study quality. RESULTS A total of 585 abstracts were screened through database searching and alternative sources. Six unique full-text studies were reviewed, of which three were excluded. Admission ionized hypocalcemia was present in up to 56.2% of the population in studies included in this review. Admission ionized hypocalcemia was also associated with increased mortality in all three studies, with increased blood transfusion requirements in two studies, and with coagulopathy in one study. CONCLUSION Hypocalcemia is a common finding in shocked trauma patients. While an association between admission ionized hypocalcemia and mortality, blood transfusion requirements, and coagulopathy has been identified, further prospective trials are essential to corroborating this association. LEVEL OF EVIDENCE Systematic review, level III.

The Global Initiative for Asthma recommends a stepwise approach to adjust asthma treatment to the needs of individual patients; inhaled corticosteroids (ICS) remain the core pharmacological treatment. However, many patients remain poorly controlled, and evidence-based algorithms to decide on the best order and rationale for add-on therapies are lacking. We explore the challenges of asthma management in primary care and review outcomes from randomised controlled trials and meta-analyses comparing the long-acting muscarinic antagonist (LAMA) tiotropium with long-acting β2-agonists (LABAs) or leukotriene receptor antagonists (LTRAs) as add-on to ICS in patients with asthma. In adults, LAMAs and LABAs provide a greater improvement in lung function than LTRAs as add-on to ICS. In children, results were positive and comparable between therapies, but data are scarce. This information could aid decision-making in primary care, supporting the use of add-on therapy to ICS to help improve lung function, control asthma symptoms and prevent exacerbations.

Summary Background Accurate prediction of exacerbation risk enables personalised care for patients with chronic obstructive pulmonary disease (COPD). We developed and validated a generalisable model to predict individualised rate and severity of COPD exacerbations. Methods In this risk modelling study, we pooled data from three COPD trials on patients with a history of exacerbations. We developed a mixed-effect model to predict exacerbations over 1 year. Severe exacerbations were those requiring inpatient care. Predictors were history of exacerbations, age, sex, body-mass index, smoking status, domiciliary oxygen therapy, lung function, symptom burden, and current medication use. Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE), a multicentre cohort study, was used for external validation. Results The development dataset included 2380 patients, 1373 (58%) of whom were men. Mean age was 64·7 years (SD 8·8). Mean exacerbation rate was 1·42 events per year and 0·29 events per year were severe. When validated against all patients with COPD in ECLIPSE (mean exacerbation rate was 1·20 events per year, 0·27 events per year were severe), the area-under-curve (AUC) was 0·81 (95% CI 0·79–0·83) for at least two exacerbations and 0·77 (95% CI 0·74–0·80) for at least one severe exacerbation. Predicted exacerbation and observed exacerbation rates were similar (1·31 events per year for all exacerbations and 0·25 events per year for severe exacerbations vs 1·20 events per year and 0·27 events per year). In ECLIPSE, in patients with previous exacerbation history (mean exacerbation rate was 1·82 events per year, 0·40 events per year were severe), AUC was 0·73 (95% CI 0·70–0·76) for two or more exacerbations and 0·74 (95% CI 0·70–0·78) for at least one severe exacerbation. Calibration was accurate for severe exacerbations (predicted 0·37 events per year vs observed 0·40 events per year) and all exacerbations (predicted 1·80 events per year vs observed 1·82 events per year). Interpretation This model can be used as a decision tool to personalise COPD treatment and prevent exacerbations. Funding Canadian Institutes of Health Research.

Blunt vertebral artery injury (VAI) is associated with severe cervicocephalic trauma and may have devastating consequences. This study aimed to determine the incidence and nature of VAI in polytrauma patients. The secondary objective was to assess the association of VAI with previously suggested risk factors. It was a retrospective observational study of all polytrauma patients admitted to the trauma unit between April 2018 and July 2019, who had CT neck angiography to diagnose blunt VAI according to modified Denver criteria. Out of 1084 admitted polytrauma patients, 1025 (94.6%) sustained blunt trauma. Of these, 120 (11.7%) underwent screening CT neck angiography. VAI was detected in 10 (8.3%; 95% CI 4.1–14.8) patients. There were three patients with Grade I injury, two with Grade II, and five with Grade IV injury. Among all trauma admissions, the incidence of diagnosed VAI was 0.9% (95% CI 0.5–1.8). Among patients suspected of VAI, there was no univariable association of VAI with C-Spine fracture: OR 4.2 (95% CI 0.51–34.4; p = 0.18). There were two (20%) deaths related to VAI. Traumatic VAI was uncommonly detected in this major trauma service in Saudi Arabia. High suspicion and liberal screening by CT angiography in cases where VAI is possible should be considered to avoid missed injuries.

Background The anti-interleukin 13 (IL-13) monoclonal antibody lebrikizumab improves lung function in patients with moderate-to-severe uncontrolled asthma, but its effects on airway inflammation and remodelling are unknown. CLAVIER was designed to assess lebrikizumab's effect on eosinophilic inflammation and remodelling. Objective To report safety and efficacy results from enrolled participants with available data from CLAVIER. Methods We performed bronchoscopy on patients with uncontrolled asthma before and after 12 weeks of randomized double-blinded treatment with lebrikizumab (n = 31) or placebo (n = 33). The pre-specified primary end-point was relative change in airway subepithelial eosinophils per mm2 of basement membrane (cells/mm2 ). Pre-specified secondary and exploratory outcomes included change in IL-13-associated biomarkers and measures of airway remodelling. Results There was a baseline imbalance in tissue eosinophils and high variability between treatment groups. There was no discernible change in adjusted mean subepithelial eosinophils/mm2 in response to lebrikizumab (95% CI, -82.5%, 97.5%). As previously observed, FEV1 increased after lebrikizumab treatment. Moreover, subepithelial collagen thickness decreased 21.5% after lebrikizumab treatment (95% CI, -32.9%, -10.2%), and fractional exhaled nitric oxide, CCL26 and SERPINB2 mRNA expression in bronchial tissues also reduced. Lebrikizumab was well tolerated, with a safety profile consistent with other lebrikizumab asthma studies. Conclusions & clinical relevance We did not observe reduced tissue eosinophil numbers in association with lebrikizumab treatment. However, in pre-specified exploratory analyses, lebrikizumab treatment was associated with reduced degree of subepithelial fibrosis, a feature of airway remodelling, as well as improved lung function and reduced key pharmacodynamic biomarkers in bronchial tissues. These results reinforce the importance of IL-13 in airway pathobiology and suggest that neutralization of IL-13 may reduce asthmatic airway remodelling. Clinical trial registration NCT02099656.

Objective Health literacy (HL) is a person’s ability to practically apply a wide range of cognitive and non-cognitive skills, to make health-related decisions. Currently, no tool applies all HL core domains to capture necessary data to measures HL in adult asthma and COPD patients. We endeavored to develop a comprehensive, function-based tool that adequately and accurately measures HL skills of this patient population. We explored the perspectives of patients related to each core HL domain, with an emphasis on self-management practices. Methods Sixteen focus groups were conducted (n = 93; 40 asthma and 53 COPD) across Canada. Data was analyzed using NVivo12. Results Thirteen subthemes were identified within five HL domains: (a) access: active access; passive access; lack of access; (b) understanding: how to improve understanding; (c) trustworthiness; relevancy and validity of information: pre- and post- application of information; (d) communication: barriers to proper communication; (e) application of information: making health decisions. Conclusions Participants provided valuable insight in terms of disease management topics and corresponding items to include in our HL tool. Practice implications Involvement of patients from initial stage allowed us to develop a tool that will serve as a first ever developed HL tool for asthma and COPD patient group.

BackgroundEndotracheal intubation (ETI) is a commonly performed but potentially high-risk procedure in the emergency department (ED). Requiring more than one attempt at intubation has been shown to increase adverse events and interventions improving first-attempt success rate should be identified to make ETI in the ED safer. We introduced and examined the effect of a targeted bundle of airway initiatives on first-attempt success and adverse events associated with ETI.MethodsThis prospective, interventional cohort study was conducted over a 2-year period at an Australian Major Trauma Centre. An online airway registry was established at the inception of the study to collect information related to all intubations. After 6 months, we introduced a bundle of initiatives including monthly audit, monthly airway management education and an airway management checklist. A time series analysis model was used to compare standard practice (ie, first 6 months) to the postintervention period.ResultsThere were 526 patients, 369 in the intervention group and 157 in the preintervention comparator group. A total of 573 intubation attempts were performed. There was a significant improvement in first-attempt success rates between preintervention and postintervention groups (88.5% vs 94.6%, relative risk 1.07; 95% CI 1.00 to 1.14, p=0.014). After the introduction of the intervention the first-attempt success rate increased significantly, by 13.4% (p=0.006) in the first month, followed by a significant increase in the monthly trend (relative to the preintervention trend) of 1.71% (pConclusionsThis bundle of airway management initiatives was associated with significant improvement in the first-attempt success rate of ETI. The introduction of a regular education programme based on the audit of a dedicated airway registry, combined with a periprocedure checklist is a worthwhile ED quality improvement initiative.

ObjectiveTo assess the rapid implementation of child neurology telehealth outpatient care with the onset of the coronavirus disease 2019 (COVID-19) pandemic in March 2020.MethodsThis was a cohort study with retrospective comparison of 14,780 in-person encounters and 2,589 telehealth encounters, including 2,093 audio-video telemedicine and 496 scheduled telephone encounters, between October 1, 2019 and April 24, 2020. We compared in-person and telehealth encounters for patient demographics and diagnoses. For audio-video telemedicine encounters, we analyzed questionnaire responses addressing provider experience, follow-up plans, technical quality, need for in-person assessment, and parent/caregiver satisfaction. We performed manual reviews of encounters flagged as concerning by providers.ResultsThere were no differences in patient age and major ICD-10 codes before and after transition. Clinicians considered telemedicine satisfactory in 93% (1,200 of 1,286) of encounters and suggested telemedicine as a component for follow-up care in 89% (1,144 of 1,286) of encounters. Technical challenges were reported in 40% (519 of 1,314) of encounters. In-person assessment was considered warranted after 5% (65 of 1,285) of encounters. Patients/caregivers indicated interest in telemedicine for future care in 86% (187 of 217) of encounters. Participation in telemedicine encounters compared to telephone encounters was less frequent among patients in racial or ethnic minority groups.ConclusionsWe effectively converted most of our outpatient care to telehealth encounters, including mostly audio-video telemedicine encounters. Providers rated the vast majority of telemedicine encounters to be satisfactory, and only a small proportion of encounters required short-term in-person follow-up. These findings suggest that telemedicine is feasible and effective for a large proportion of child neurology care. Additional strategies are needed to ensure equitable telemedicine use.

Breast cancer stem cells (BCSCs) are competent to initiate tumor formation and growth and refractory to conventional therapies. Consequently BCSCs are implicated in tumor recurrence. Many signaling cascades associated with BCSCs are critical for epithelial-to-mesenchymal transition (EMT). We developed a model system to mechanistically examine BCSCs in basal-like breast cancer using MCF10AT1 FACS sorted for CD24 (negative/low in BCSCs) and CD44 (positive/high in BCSCs). Ingenuity Pathway Analysis comparing RNA-seq on the CD24-/low versus CD24+/high MCF10AT1 indicates that the top activated upstream regulators include TWIST1, TGFβ1, OCT4, and other factors known to be increased in BCSCs and during EMT. The top inhibited upstream regulators include ESR1, TP63, and FAS. Consistent with our results, many genes previously demonstrated to be regulated by RUNX factors are altered in BCSCs. The RUNX2 interaction network is the top significant pathway altered between CD24-/low and CD24+/high MCF10AT1. RUNX1 is higher in expression at the RNA level than RUNX2. RUNX3 is not expressed. While, human-specific quantitative polymerase chain reaction primers demonstrate that RUNX1 and CDH1 decrease in human MCF10CA1a cells that have grown tumors within the murine mammary fat pad microenvironment, RUNX2 and VIM increase. Treatment with an inhibitor of RUNX binding to CBFβ for 5 days followed by a 7-day recovery period results in EMT suggesting that loss of RUNX1, rather than increase in RUNX2, is a driver of EMT in early stage breast cancer. Increased understanding of RUNX regulation on BCSCs and EMT will provide novel insight into therapeutic strategies to prevent recurrence.

The authors perform a retrospective trauma registry study to compare clinical, surgical and radiographical variables between anterior and posterior approaches in the management of AO Type B1 and B2 traumatic thoracolumbar fractures. Consecutive patients with surgically-managed AO Type B1 and B2 thoracolumbar fractures were included. Baseline demographics, surgical outcomes (including duration of surgery, postoperative morbidity etc.), neurological outcomes and radiographical outcomes (Cobb angle, Gardner angle) were compared between the anterior and posterior approaches. A total of 108 patients (anterior: n = 25, posterior: n = 83) were included. There were no significant between-group differences in baseline demographics and co-morbidities. Duration of surgery was longer in the anterior compared to posterior group (251 ± 91 min vs. 175 ± 69 min respectively, p 0.00003). At six-months post-surgery, there was a trend towards improvement of at least one AIS grade in the posterior compared to the anterior group (85.7% vs. 33.3% respectively, p = 0.08). Postoperative complication profile showed no difference between approaches. The posterior approach resulted in better sagittal correction (Cobb angle; anterior: +1.05 ± 8.61 deg, posterior: -3.87 ± 9.88 deg, p = 0.03) and smaller loss of correction at 6-months post-surgery (Cobb angle; anterior: 8.36 ± 9.47 deg, posterior: 4.88 ± 6.62 deg, p = 0.048). This is the first study investigating surgical approach in flexion-distraction thoracolumbar fractures. Besides a shorter operative duration, the posterior approach seems to portend more favourable radiological correction at 6 months when compared to the anterior approach. Given the inherent selection bias of this study, definitive recommendations regarding the anterior versus posterior approach cannot be made. Further well-defined, prospective studies are necessary.

Background Trauma registries are essential to trauma systems, to enable collection of the data needed to enhance clinical knowledge and monitor system performance. The King Saud Medical City (KSMC) in Riyadh, Kingdom of Saudi Arabia (KSA) is aiming to become a Level 1 Trauma Centre, and required a trauma registry in order to do so. Our objective was to establish the Saudi TraumA Registry (STAR) at the (KSMC) and ready it for national deployment. The challenge was that no formal trauma data collection had occurred previously and clinicians had no prior experience of trauma registries. Methods To develop the registry, a novel 12 step implementation plan was created and followed at the KSMC. Registry criteria and a Minimum Dataset were selected; training was delivered; database specifications were written; operating procedures were developed and regular reporting was initiated. Results Data collection commenced on August 1st 2017. The registry was fully operational by April 2018, eight months ahead of schedule. During the first year of data collection an average of 216 records per month were entered into the database. An inaugural report was presented at the Saudi Trauma Conference in February 2019. Conclusions The strategy deployed at the KSMC has successfully established the STAR. In the short term, process indicators will track the development of the hospital into a Level 1 Trauma Centre. In the medium to long term the STAR will be rolled out nationally to capture the impact of public health initiatives aimed at reducing injury in the KSA. The effect of the STAR will be that the country is better equipped to deliver continuous improvements in trauma systems and quality of care.

BACKGROUND CONTEXT There are three phases in prophylaxis of surgical site infections (SSI): preoperative, intraoperative and postoperative. There is lack of consensus and paucity of evidence with SSI prophylaxis in the postoperative period. PURPOSE To systematically evaluate the literature, and provide evidence-based summaries on postoperative measures for SSI prophylaxis in spine surgery. STUDY DESIGN Systematic review, meta-analysis, evidence synthesis. METHODS A systematic review conforming to PRIMSA guidelines was performed utilizing PubMed (MEDLINE), EMBASE, and the Cochrane Database from inception to January 2019. The GRADE approach was used for quality appraisal and synthesis of evidence. Six postoperative care domains with associated key questions were identified. Included studies were extracted into evidence tables, data synthesized quantitatively and qualitatively, and evidence appraised per GRADE approach. RESULTS Forty-one studies (nine RCT, 32 cohort studies) were included. In the setting of preincisional antimicrobial prophylaxis (AMP) administration, use of postoperative AMP for SSI reduction has not been found to reduce rate of SSI in lumbosacral spine surgery. Prolonged administration of AMP for more than 48 hours postoperatively does not seem to reduce the rate of SSI in decompression-only or lumbar spine fusion surgery. Utilization of wound drainage systems in lumbosacral spine and adolescent idiopathic scoliosis corrective surgery does not seem to alter the overall rate of SSI in spine surgery. Concomitant administration of AMP in the presence of a wound drain does not seem to reduce the overall rate of SSI, deep SSI, or superficial SSI in thoracolumbar fusion performed for degenerative and deformity spine pathologies, and in adolescent idiopathic scoliosis corrective surgery. Enhanced-recovery after surgery clinical pathways and infection-specific protocols do not seem to reduce rate of SSI in spine surgery. Insufficient evidence exists for other types of spine surgery not mentioned above, and also for non-AMP pharmacological measures, dressing type and duration, suture and staple management, and postoperative nutrition for SSI prophylaxis in spine surgery. CONCLUSIONS Despite the postoperative period being key in SSI prophylaxis, the literature is sparse and without consensus on optimum postoperative care for SSI prevention in spine surgery. The current best evidence is presented with its limitations. High quality studies addressing high risk cohorts such as the elderly, obese, and diabetic populations, and for traumatic and oncological indications are urgently required.

Objective To quantify the pharmacodynamic (PD) activity of daily subcutaneous (SC) enoxaparin as venous thromboembolism (VTE) prophylaxis in high-risk trauma patients admitted to the intensive care unit (ICU). Methods This was a prospective observational PD study conducted in the ICU of a state-wide major trauma referral centre. The study cohort included adult patients admitted to the ICU with a high risk of VTE, as defined by at least one of the following: age > 40 years, prior VTE, spinal cord injury (SCI), traumatic brain injury (TBI), major venous injury, pelvic fractures, spinal fractures requiring treatment, severe lower limb injuries, and major surgery >2 h in duration. Standard prophylactic enoxaparin dosing was 40 mg SC daily, unless amended by the treating clinician. Plasma anti-Xa activity was measured approximately 60 min before dosing (trough activity), and at 3–5 h after dosing (peak activity). Target peak and trough activity were defined as >0.2 IU/mL and >0.1 IU/mL respectively. Clinical data including the development of VTE and haemorrhagic complications were collected. Results Twenty-five patients were enrolled. Median [IQR] age, weight, and plasma creatinine were 59 years [36,70], 85 kg [76.5,93.5] and 70μmol/L [60.5,109] respectively. Median APACHE III and Injury Severity Score were 54 [42.5,66.5] and 27 [17,34] respectively. Thirteen patients suffered a TBI, in 12 cases surgery extended beyond two hours, and five patients had spinal fractures requiring treatment. Twenty-two patients received enoxaparin 40 mg SC daily, two 60 mg, and one 20 mg. Median peak and trough anti-Xa activity was 0.21 IU/mL [0.125,0.25] and 0.01 IU/mL [0,0.05] respectively. Twelve (12/25; 48%) patients had low peak activity ≤0.2 IU/mL. Twenty-one (21/23; 91%) patients had low trough activity (≤0.1 IU/mL) and in six (6/23; 26%) cases, these were undetectable. Eight (8/25; 32%) patients had documented VTE of whom seven had low trough activity. There were no major haemorrhagic complications. Conclusions In a cohort of high risk critically ill trauma patients receiving daily SC enoxaparin as VTE chemoprophylaxis, measured peak and trough plasma anti-Xa activity was inadequate in a significant proportion. On this basis, further systematic investigation concerning dose optimisation in this patient population appears warranted.

The actual burden of COPD and asthma may be much higher than appreciated, since a large proportion of individuals are not diagnosed. Our study objective was to compare health care utilization, burden of symptoms and quality of life in subjects with self-reported respiratory symptoms who were subsequently found to have undiagnosed airflow obstruction compared to those having no airflow obstruction.This cross-sectional case-finding study used data from the Undiagnosed COPD and Asthma Population (UCAP) study. Adult subjects with respiratory symptoms who had no history of diagnosed lung disease were recruited in a two-step case-finding process using random digit-dialling of land lines and cell phones located within a 90-min radius of 16 Canadian study sites. Participants were assessed for COPD, asthma or no airflow obstruction using pre- and post-bronchodilator spirometry based on American Thoracic Society diagnostic criteria.1660 participants were recruited, of these 1615 had adequate spirometry and 331 (20.5%) subjects met spirometry criteria for undiagnosed asthma or COPD. Subjects with undiagnosed asthma or COPD had increased respiratory symptoms as assessed by the COPD Assessment Test (CAT), and higher St. George's Respiratory Questionnaire (SGRQ) scores indicating worse health-related quality of life, compared to subjects with no airflow obstruction. No between-group differences were found in health care utilization or work or school absenteeism.Undiagnosed asthma and COPD are common in Canadian adults experiencing breathing problems and are associated with a greater burden of symptoms and poorer health-related quality of life. These results suggest that patients may benefit from early identification and treatment of undiagnosed asthma and COPD.

The aim of this study was to assess pain and quality of life (QoL) outcomes in patients with multiple painful displaced fractured ribs with and without operative fixation. Rib fractures are common and can lead to significant pain and disability. There is minimal level 1 evidence for rib fixation in non-ventilator-dependent patients with chest wall injuries. We hypothesized that surgical stabilization of rib fractures would reduce pain and improve QoL during 6 months.A prospective multicenter randomized controlled trial comparing rib fixation to nonoperative management of nonventilated patients with at least three consecutive rib fractures was conducted. Inclusion criteria were rib fracture displacement and/or ongoing pain. Pain (McGill Pain Questionnaire) and QoL (Short Form 12) at 3 and 6 months postinjury were assessed. Surgeons enrolled patients in whom they felt there was clinical equipoise. Patients who were deemed to need surgical fixation or who were deemed to be too well to be randomized to rib fixation were not enrolled.A total of 124 patients were enrolled at four sites between 2017 and 2020. Sixty-one patients were randomized to operative management and 63 to nonoperative management. No differences were seen in the primary endpoint of Pain Rating Index at 3 months or in the QoL measures. Return-to-work rates improved between 3 and 6 months, favoring the operative group.In this study, no improvements in pain or QoL at 3 and 6 months in patients undergoing rib fixation for nonflail, non-ventilator-dependent rib fractures have been demonstrated.Therapeutic/Care Management; Level II.

The wide-spread use of an initial 'Glasgow Coma Scale (GCS) 8 or less' to define and dichotomise 'severe' from 'mild' or 'moderate' traumatic brain injury (TBI) is an out-dated research heuristic that has become an epidemiological convenience transfixing clinical care. Triaging based on GCS can delay the care of patients who have rapidly evolving injuries. Sole reliance on the initial GCS can therefore provide a false sense of security to caregivers and fail to provide timely care for patients presenting with GCS greater than 8. Nearly 50 years after the development of the GCS - and the resultant misplaced clinical and statistical definitions - TBI remains a heterogeneous entity, in which 'best practice' and 'prognoses' are poorly stratified by GCS alone. There is an urgent need for a paradigm shift towards more effective initial assessment of TBI.

International audience; BackgroundAcute exacerbations of chronic obstructive pulmonary disease (AECOPD) are associated with changes in the sputum microbiome, including an increased prevalence of pathogenic bacteria. Vaccination against the most frequent bacteria identified in AECOPD might reduce exacerbation frequency. We assessed the efficacy, safety, and immunogenicity of a candidate vaccine containing surface proteins from non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) in patients with COPD.MethodsThis multicentre, randomised, observer-blinded, placebo-controlled, proof-of-concept, phase 2b trial recruited patients with stable COPD, moderate-to-very severe airflow limitation (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 2, 3, or 4), at 67 clinical sites in Belgium, Canada, France, Germany, Italy, Spain, UK, and USA. Eligible patients were aged 40–80 years and had a history of at least one moderate or severe exacerbation in the previous year. Patients were allocated (1:1) using a minimisation algorithm to receive two intramuscular injections of NTHi–Mcat vaccine or placebo 60 days apart, in addition to standard care. The allocation algorithm considered age category, number of previous exacerbations, COPD severity at study entry, and country as minimisation factors, to guarantee treatment balance within each factor. Vaccine recipients and those responsible for evaluating study endpoints were masked to group allocation. In the analysis of efficacy, the primary outcome was the rate of any moderate or severe AECOPD occurring within a 1-year period, starting 1 month after the second dose in patients who received two vaccine doses (modified total vaccinated cohort). Safety was assessed in the total vaccinated cohort. The trial is registered with ClinicalTrials.gov, number NCT03281876, and is complete.FindingsBetween Nov 27, 2017, and Nov 30, 2018, 606 adults were enrolled and included in the total vaccinated cohort (304 in the NTHi–Mcat vaccine group, 302 in the placebo group); 571 received two doses and were included in the primary efficacy analysis (279 in the NTHi–Mcat vaccine group, 292 in the placebo group). 23 participants dropped-out in the NTHi–Mcat vaccine group and 39 in the placebo group; this included 4 patients in the NTHi–Mcat vaccine group and 15 in the placebo group who withdrew from the study because of an adverse event. The primary analysis included 340 exacerbations (in follow-up time 102 123 days) in the NTHi–Mcat vaccine group and 333 (in 104 443 days) in the placebo group, with a yearly rate of moderate or severe AECOPD of 1·22 in the NTHi–Mcat vaccine group and 1·17 in the placebo group, with vaccine efficacy in reducing the yearly rate of moderate or severe AECOPD estimated to be zero (vaccine efficacy point estimate 2·26% [87% CI –18·27 to 11·58]; p=0·82). Solicited local adverse events were more frequent in the NTHi–Mcat vaccine group (216 [72%] of 301 patients) than with placebo (34 [11%] of 299 patients), and the frequency of solicited general adverse events was similar between groups (239 [79%] of 301 vs 235 [79%] of 299 patients). There was one death in the NTHi–Mcat vaccine group (acute respiratory failure, not related to vaccination) and ten in the placebo group (seven due in part to COPD or respiratory failure). There were 158 serious adverse events (89 [29%] of 304 patients) in the NTHi–Mcat vaccine group, not related to vaccination, and 214 (99 [33%] of 302 patients) in the placebo group.InterpretationNTHi–Mcat vaccine administered to patients with COPD did not show efficacy in reducing the yearly rate of moderate or severe exacerbations. No safety concerns were identified.

Background: ANDHI was done to assess the efficacy of benralizumab, including onset of effect and impact on health-related quality of life (HRQOL), exacerbation rate, lung function, and nasal polyposis symptoms. Methods: This phase 3b, randomised, double-blind, parallel-group, placebo-controlled ANDHI study was completed in adults (aged 18–75 years) with severe eosinophilic asthma with at least 2 exacerbations in the previous year, despite high-dose inhaled corticosteroid plus additional controllers, screening blood eosinophil counts of at least 150 cells per μL, and an Asthma Control Questionnaire 6 (ACQ-6) score of 1·5 or more. Patients who met eligibility criteria were randomly assigned (2:1; stratified by previous exacerbation count [two, or three or more], maintenance oral corticosteroid use, and region), using an integrated web-based response system, to receive benralizumab at 30 mg every 8 weeks (first three doses given 4 weeks apart) or matched placebo for 24 weeks. Primary efficacy measure was annualised asthma exacerbation rate, with rate ratio (RR) calculated over the approximate 24-week follow-up. Secondary efficacy measures included change from baseline to end of treatment (week 24) in St George's Respiratory Questionnaire (SGRQ) total score (key secondary endpoint), FEV1, peak expiratory flow (PEF), ACQ-6, Predominant Symptom and Impairment Assessment (PSIA), Clinician Global Impression of Change (CGI-C), Patient Global Impression of Change (PGI-C), and Sino-Nasal Outcome Test-22 (SNOT-22). All efficacy analyses, except for SNOT-22, were summarised and analysed using the full analysis set on an intention-to-treat population (all randomly assigned patients receiving investigational product, regardless of protocol adherence or continued participation in the study). SNOT-22 was summarised for the subgroup of patients with physician-diagnosed nasal polyposis with informed consent. This study is registered with ClinicalTrials.gov, NCT03170271. Findings: Between July 7, 2017, and Sept 25, 2019, 656 patients received benralizumab (n=427) or placebo (n=229). Baseline characteristics were consistent with severe eosinophilic asthma. Benralizumab significantly reduced exacerbation risk by 49% compared with placebo (RR estimate 0·51, 95% CI 0·39–0·65; p5%) were nasopharyngitis (30 [7%]), headache (37 [9%]), sinusitis (28 [7%]), bronchitis (22 [5%]), and pyrexia (26 [6%]). Fewer serious adverse events were reported for benralizumab (23 [5%]) versus placebo (25 [11%]), and the only common serious adverse event (experienced by >1% of patients) was worsening of asthma, which was reported for nine (2%) patients in the benralizumab group and nine (4%) patients in the placebo group. Interpretation: Our results extend the efficacy profile of benralizumab for patients with severe eosinophilic asthma, showing early clinical benefits in patient-reported outcomes, HRQOL, lung function, and nasal polyposis symptoms. Funding: AstraZeneca.

International audience; Severe asthma often remains uncontrolled despite effective treatments and evidence-based guidelines. A group of global experts in asthma and biologic medications from nine countries considered the most relevant clinical variables to manage severe asthma in adult patients and guide treatment choice. The resulting recommendations address the investigation of biomarker levels (blood eosinophil count along with fractional concentration of exhaled nitric oxide [FeNO]), clinical features (oral corticosteroid [OCS] dependency, specific comorbid disease entities associated with severe type 2 asthma), and safety considerations. Current evidence suggests that biomarkers, including both blood or sputum eosinophil counts as well as FeNO, add prognostic and predictive value and should be measured in all patients with severe asthma. OCS use is an important factor in biologic selection, especially given the documented ability of some biologics to reduce OCS dependency. Comorbid diseases and relevant safety considerations to each biologic should also be considered. More data are needed to determine whether biomarker profiles identify patients suited to one biologic versus another as limited data support differential predictors of response. Further prospective head-to-head trials and post hoc analyses of clinical trial data are warranted. The authors believe these recommendations have value as they offer expert opinion to assist health care providers in making difficult decisions regarding the quality of care in severe, type 2 asthma with biologic medications. They remain conditional and are based on limited data owing to a lack of head-to-head comparisons.

Funder: Global Initiative for Asthma, The Global Initiative for Asthma (GINA) Strategy Report provides clinicians with an annually updated evidence-based strategy for asthma management and prevention, which can be adapted for local circumstances (e.g., medication availability). This article summarizes key recommendations from GINA 2021, and the evidence underpinning recent changes. GINA recommends that asthma in adults and adolescents should not be treated solely with short-acting β2 -agonist (SABA), because of the risks of SABA-only treatment and SABA overuse, and evidence for benefit of inhaled corticosteroids (ICS). Large trials show that as-needed combination ICS-formoterol reduces severe exacerbations by ≥60% in mild asthma compared with SABA alone, with similar exacerbation, symptom, lung function, and inflammatory outcomes as daily ICS plus as-needed SABA. Key changes in GINA 2021 include division of the treatment figure for adults and adolescents into two tracks. Track 1 (preferred) has low-dose ICS-formoterol as the reliever at all steps: as needed only in Steps 1-2 (mild asthma), and with daily maintenance ICS-formoterol (maintenance-and-reliever therapy, "MART") in Steps 3-5. Track 2 (alternative) has as-needed SABA across all steps, plus regular ICS (Step 2) or ICS-long-acting β2 -agonist (Steps 3-5). For adults with moderate-to-severe asthma, GINA makes additional recommendations in Step 5 for add-on long-acting muscarinic antagonists and azithromycin, with add-on biologic therapies for severe asthma. For children 6-11 years, new treatment options are added at Steps 3-4. Across all age groups and levels of severity, regular personalized assessment, treatment of modifiable risk factors, self-management education, skills training, appropriate medication adjustment, and review remain essential to optimize asthma outcomes.

The Global Initiative for Asthma report recommends consideration of add-on biologics for patients with type 2 inflammation (blood eosinophils ≥150 cells/μL, fractional exhaled nitric oxide [Feno] ≥20 parts per billion or allergic asthma) whose asthma cannot be controlled by high-dose inhaled corticosteroids. In QUEST (NCT02414854), add-on dupilumab versus placebo was efficacious in patients with uncontrolled, moderate to severe asthma, including those with eosinophils greater than or equal to 150 cells/μL and/or Feno greater than or equal to 25 parts per billion.To assess dupilumab efficacy in patients with a type 2 phenotype in the presence or absence of allergic asthma phenotype.Patients aged 12 years or older received add-on dupilumab 200/300 mg versus matched placebo every 2 weeks for 52 weeks. Allergic asthma phenotype was defined as baseline serum total IgE greater than or equal to 30 IU/mL and 1 or more perennial aeroallergen-specific IgE level greater than or equal to 0.35 kU/L. Annualized rate of severe asthma exacerbations and changes from study baseline in prebronchodilator and postbronchodilator FEVOf 1902 patients in QUEST, 83.3% had eosinophils and/or Feno above Global Initiative for Asthma thresholds; 56.9% had evidence for allergic asthma. Dupilumab significantly reduced the rate of severe asthma exacerbations in patients with (48.8%) and without (64.0%) evidence of allergic asthma and improved prebronchodilator and postbronchodilator FEVIn patients with type 2 biomarkers over Global Initiative for Asthma thresholds, dupilumab significantly reduced exacerbations and improved lung function. Efficacy was not impacted by allergic status.

We aimed to determine the incidence of periodic and rhythmic patterns (PRP), assess the interrater agreement between electroencephalographers scoring PRP using standardized terminology, and analyze associations between PRP and electrographic seizures (ES) in critically ill children.This was a prospective observational study of consecutive critically ill children undergoing continuous electroencephalographic monitoring (CEEG). PRP were identified by one electroencephalographer, and then two pediatric electroencephalographers independently scored the first 1-h epoch that contained PRP using standardized terminology. We determined the incidence of PRPs, evaluated interrater agreement between electroencephalographers scoring PRP, and evaluated associations between PRP and ES.One thousand three hundred ninety-nine patients underwent CEEG. ES occurred in 345 (25%) subjects. PRP, ES + PRP, and ictal-interictal continuum (IIC) patterns occurred in 142 (10%), 81 (6%), and 93 (7%) subjects, respectively. The most common PRP were generalized periodic discharges (GPD; 43, 30%), lateralized periodic discharges (LPD; 34, 24%), generalized rhythmic delta activity (GRDA; 34, 24%), bilateral independent periodic discharges (BIPD; 14, 10%), and lateralized rhythmic delta activity (LRDA; 11, 8%). ES risk varied by PRP type (p .01). ES occurrence was associated with GPD (odds ratio [OR] = 6.35, p .01), LPD (OR = 10.45, p .01), BIPD (OR = 6.77, p .01), and LRDA (OR = 6.58, p .01). Some modifying features increased the risk of ES for each of those PRP. GRDA was not significantly associated with ES (OR = 1.34, p = .44). Each of the IIC patterns was associated with ES (OR = 6.83-8.81, p .01). ES and PRP occurred within 6 h (before or after) in 45 (56%) subjects.PRP occurred in 10% of critically ill children who underwent CEEG. The most common patterns were GPD, LPD, GRDA, BIPD, and LRDA. The GPD, LPD, BIPD, LRDA, and IIC patterns were associated with ES. GRDA was not associated with ES.